Researchers at the University of Chicago have developed a new synthetic molecule that shows promise in targeting transcription factors, proteins that enable cancer to spread throughout the body. This breakthrough, published in Nature Chemical Biology, could lead to new treatment options for cancer.
Raymond Moellering, a professor of chemistry at UChicago and co-senior author on the study, likened targeting transcription factors to "leaving the solar system for humans," highlighting its significance in cancer therapies. The research focuses on hypoxia-inducible transcription factors (HIFs), which help tumor cells survive by spreading when deprived of oxygen.
Marsha Rosner, another co-senior author and distinguished service professor at UChicago, explained that these factors enable metastasis. Designing drugs to stop them has been challenging due to their unusual configuration. Moellering's team approached this problem by creating a synthetic molecule that mimics molecular "claws" used by transcription factors to latch onto DNA. This innovation blocks rogue proteins from altering cell instructions.
The team tested their approach on mice with triple-negative breast cancer using a molecule targeting XBP-1, a factor involved in cancer. The results showed tumor shrinkage and reduced metastasis without toxic side effects.
Long Nguyen, a postdoctoral researcher and co-first author of the paper, noted that the molecule blocked multiple transcription factors from functioning at DNA sites. Moellering added that this approach could prevent transcription factors from substituting for each other.
Though further steps are needed before human application, researchers are optimistic about using these molecules in experiments to better understand how transcription factors work in cancer and other diseases. Rosner emphasized the importance of HIFs as fundamental parts of cellular response to low oxygen levels.
The study included contributions from several UChicago researchers and received funding from various organizations including the U.S. Department of Defense and National Institutes of Health.
Citation: “Direct inhibition of tumor hypoxia response with synthetic transcriptional repressors.” Qiao and Long et al., Nature Chemical Biology, Aug. 30, 2024.